Cryptic mutations could be evolution’s hidden fuel

The transformation of raw genetic material on a laboratory bench has provided a rare empirical demonstration of processes that may be universally crucial to evolution, but are only beginning to be understood.

The processes, called cryptic variation and preadaptation, involve mutations that don’t affect an organism when they first occur, and are initially exempt from pressures of natural selection. As they gather, however, at some later date, they could combine to form the basis for complex, unpredictable new traits.

In the new study, the ability of evolving, chemical-crunching molecules called ribozymes to adapt in new environments proved directly related to earlier accumulations of cryptic mutations. The details are esoteric, but their implications involve the very essence of adaptation and evolution.

“It’s one of the more modern topics in evolutionary theory,” said mathematical biologist Joshua Plotkin of the University of Pennsylvania, author of a commentary on the experiment, which was described June 2 in Nature. “The idea has been around for a while, but direct evidence hasn’t been found until recently.”

The experiment was led by evolutionary biologists Eric Hayden and Andreas Wagner of Switzerland’s University of Zurich, who use ribozymes—molecules made from RNA, a single-stranded form of genetic material—to study evolutionary principles in the simplest possible way.

Two of those principles are cryptic variation and preadaptation, which were first proposed in the mid-20th century and conceptually refined in the mid-1970s. They were logical answers to the question of how complex traits, seemingly far too complex to be explained by one or a few mutations, could arise.

But even as such leading thinkers as Stephen Jay Gould embraced the concept, it proved difficult to study in detail. The tools didn’t exist to interpret genetic data with the necessary rigor. The concept itself was also difficult to grasp, injecting long periods of accumulation and purposeless mutations into an evolutionary narrative supposedly driven by constant selection.

In recent years, however, with the advent of better tools and a growing appreciation for evolution’s sheer complexity, researchers’ attention has turned again to cryptic variation and preadaptation. Computer models and scattered observations in bacteria and yeast hinted at their importance. But definitive proof, combining exhaustive genetic observation with real-world evolution, was elusive.

“Cryptic variation addresses questions of innovation. How do new things come about in biology?” said Hayden. “There’s been a long history of this concept, but no concrete experimental demonstration.”

In the new study, Hayden and Wagner evolved ribozymes in test tubes of chemicals, then moved them to a new chemical substrate, a shift analogous to requiring animals to suddenly subsist on a new food source.

The ribozymes that flourished were those that had accumulated specific sets of cryptic mutations in their former environment. Those variations, seemingly irrelevant before, became the basis of newly useful adaptation. The researchers were able to measure every change in detail.

“It is a groundbreaking proof of principle,” said University of Arizona evolutionary biologist Joanna Masel, who wasn’t involved in the study. “This study is a clear demonstration that cryptic genetic variation can make evolution more effective.”

According to Plotkin, cryptic variation and preadaptation may be crucial to the evolution of drug resistance and immune system evasion in pathogens. Rather than looking for straightforward mutations, researchers could search for combinations, perhaps developing an “advance warning system” to flag seemingly innocuous changes.

Another application could be in genetic engineering. Whereas virus and bacteria designers tend to “accept any mutations that get them closer to their intended outcome,” said Plotkin, “it might be important to take lateral steps as well as uphill steps.”

Cryptic variation and preadaptation could also be important to the evolution of animals, from the origin of multicellularity to complex features like eyes and language. Plotkin would like to see studies revisiting the evolution of Charles Darwin’s famous finch beaks, but with an eye towards these newly described processes.

Masel said that better understanding cryptic variation and preadaptation could help programmers of evolving computer systems, and perhaps explain why some systems are better able than others to evolve. “Why are biological systems so evolvable?” she said. “This dynamic may or may not be the essence of evolvability. That’s certainly one of the hypotheses out there, and I am enthusiastic about it.”

“My prediction is that it is good to foster lots of variation,” said Masel, who likened cryptic variation and preadaptation to Google’s famous requirement that employees spend 20 percent of their time on projects of personal whimsy. Rather than focusing narrowly on ideas that are obviously good, “Foster circumstances where lots of non-terrible ideas are floating around,” said Masel.